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Nailing B urkitt lymphoma

2012; Wiley; Volume: 156; Issue: 6 Linguagem: Inglês

10.1111/j.1365-2141.2012.09055.x

1365-2141

Dennis H. Wright,

Histiocytic Disorders and Treatments

‘Uganda is a fairyland. You can climb up a railway instead of a beanstalk and at the end there is a wonderful new world’. Winston Churchill wrote these words at the beginning of the 20th century, describing Uganda as the pearl of Africa. Had he climbed the beanstalk in the middle of the century he would have found another bright jewel in the form of Makerere University of Medical School and Mulago Hospital, its associated teaching hospital. These two institutions had a high reputation throughout Africa and beyond, with staff, including Denis Burkitt, actively engaged in research in many areas of medicine. Denis Burkitt was born in County Fermanagh, Northern Ireland where his father, James Burkitt, was the County Engineer. His was a deeply religious family and Denis's Christian conviction acted as his guide throughout this life. James Burkitt was famous as a pioneering ornithologist and one of the first to use leg rings to identify individual birds and to study their behaviour and distribution. This may have had an influence on Denis's later epidemiological studies, although he never followed his father's interest in ornithology. This may have been due to the fact that, at the age of 11 years, he lost his right eye following a stone throwing fight between two gangs of boys (in later years it was said that Burkitt went to Africa with one eye but saw more than most men with two eyes). In 1929 Burkitt entered Trinity College, Dublin to study engineering. However, during his first year he became convinced that his calling was to medicine and he enrolled as a medical student. He had a distinguished undergraduate career and was placed second in the final qualifying examination. After appointments in Ireland and England, Burkitt passed the examination for the Fellowship of the Royal College of Surgeons of Edinburgh. His next adventure was to sign up as ship's surgeon aboard a freighter of the Blue Funnel Line on a 5 month return trip to Manchuria. He had time to think about his future on this journey and formulated the view that his future lay as a surgeon in the developing world. On return to England, he was appointed as Residential Surgical Officer at the Prince of Wales Hospital, Plymouth. Here he met nurse Olive Rogers, who later became his wife. In 1940 Burkitt applied to join the Royal Army Medical Corps (RAMC) but was rejected. The next year he applied to the Colonial Office for service in West Africa but was again rejected. A second application to join the RAMC was however accepted. After training in the UK he embarked for Mombasa and served in Kenya and Somalia. During this time he was able to make a 6 week visit to Uganda. After postings to Ceylon and Singapore he returned to England for demobilization convinced that he had been called to work in Uganda. Burkitt's second application to the Colonial Office was successful and he was appointed to the post of Medical Officer at Lira, in the Lango District of Uganda, responsible for the medical needs of 300 000 people. In 1948 he was appointed as a surgical specialist to Mulago Hospital, Kampala and Honorary Teacher in Clinical Surgery, Makerere University College Medical School. In his early years in Uganda Burkitt made a major contribution to the management of orthopaedic diseases resulting from poliomyelitis and tropical leg ulcers. In particular, he organized the production of callipers and crutches from cheap, locally available materials. In 1957, Hugh Trowell, a senior physician at Mulago, asked Burkitt to see a 5-year-old boy with tumours in all four quadrants of the jaw. A month later, while visiting Jinja Hospital, Burkitt saw a young girl with jaw tumours similar to the case seen in Kampala. This girl was transferred to Mulago Hospital where it was established that she had abdominal as well as facial tumours. Both children died. These two cases acted as the catalyst that prompted Burkitt to study the lymphoma that bears his name. He found further cases in the records of Mulago Hospital and established that the jaw tumours and abdominal tumours were part of a single disease entity and not separate entities as was often thought at that time. A later analysis of cases showed that the jaw involvement is age-related, with 100% of cases at the age of 3 years having jaw tumours falling to <20% in the teen years (Burkitt, 1970). As the median age of cases of Burkitt lymphoma patients in Uganda was 7 years, approximately 50% showed jaw involvement. Burkitt's first clinical description of the tumour was published in 1958 in the British Journal of Surgery and appeared to receive little attention (Burkitt, 1958). More detailed descriptions of the clinical and pathological features (Burkitt & O'Conor, 1961; O'Conor, 1961) attracted much more international attention. Review of the medical literature from sub-Saharan Africa showed reports of small numbers of cases with clinical features of Burkitt lymphoma categorized either as small round cell tumours or as unusual variants of neuroblastoma. The detailed case notes of Sir Albert Cook, the first missionary surgeon to practice in Uganda, describe and illustrate in drawings cases with the typical clinical features of Burkitt lymphoma, indicating that the tumour was present in Uganda at the beginning of the 20th century. Burkitt's second major contribution to the study of the tumour that bears his name was to determine its distribution in Africa. This was a daunting task at that time but it was aided by the distinctive clinical features of the tumour. On a shoe-string budget he sent illustrated circulars to hospitals throughout Africa establishing that the tumour had been seen in a sub-Saharan belt across Africa with a tail extending down the east coast but otherwise absent from South Africa. Having been told by George Oettle of the South African Institute for Medical Research, Johannesburg, that that he had not seen the tumour in South Africa, Burkitt organized a long safari. Accompanied by two missionary doctor friends, travelling in a reinforced second-hand Ford car they journeyed through East and Central Africa to Johannesburg and back, visiting hospitals, interviewing the medical staff and examining their records to determine the tumour distribution. These investigations showed that the tumour appeared to be altitude-dependent and that the critical altitude fell as the distance from the equator increased. This indicated that temperature was a critical factor (Burkitt, 1962). Further travels to West Africa established that the tumour was absent from areas with a low rainfall (Dalldorf et al, 1964). This distribution within the wet tropics is similar to the distribution of yellow fever and raised the possibility that a mosquito-vectored virus might be implicated in the aetiology of the tumour (Haddow, 1970). The Epstein–Barr virus (EBV), that was eventually isolated from and is present in all cases of endemic Burkitt lymphoma, is worldwide in its distribution and cannot be responsible for the geographical distribution of the tumour (Epstein et al, 1964). The restriction of endemic Burkitt lymphoma to the wet tropics is now thought to be due to the presence of holoendemic falciparum malaria. Recent studies have shown that the membrane protein produced by Plasmodium falciparum activates B-cells and reactivates latent EBV infection (Chêne et al, 2007). It has been suggested that malaria and EBV together activate the mutation generating enzyme activation-induced deaminase, responsible for somatic hypermutation and isotype switching in immunoglobulin genes and that this leads to MYC-translocation (Thorley-Lawson & Duca, 2007). The ability of Plasmodium falciparum to immortalize B-cells may then create a permissive environment for tumour development. When Burkitt began working in Uganda there was no treatment for lymphoma other than surgery. His 1958 paper, showing the widespread distribution of the tumour, even in the four cases that appeared to be localized to the jaws, demonstrated the futility of surgery as a curative option (Burkitt, 1958). With no radiotherapy available in East Africa, chemotherapy was the only option available but this was not an easy solution for a surgeon with no training in chemotherapy in a country without supplies of chemotherapeutic drugs. Undeterred, Burkitt sought advice and drugs from American friends and drug companies. All cells in Burkitt lymphoma are in cycle and sensitive to chemotherapy and the results of treatment with single agents were often dramatic, with a significant number of long term remissions (Wright et al, 1966a). In 1963, the Union for International Cancer Control organized a symposium on lymphoreticular tumours in Africa to be held in Dakar, Senegal. Burkitt and myself were invited to present papers. Burkitt suggested that we enlist the help of the East African Medical Research Foundation flying doctor service to hop through a number of West African states on the way to Dakar to assess their experience of lymphomas. We filled up our passports with entry permits to francophone West African states in preparation for this adventure. Unfortunately, the Senegal authorities refused an entry permit for George Oettle because of his South African nationality. The meeting was transferred to the United Nations Educational, Scientific and Cultural Organization building in a very cold Paris and the delegates came from East and West Africa, Europe and America. Burkitt lymphoma was often called African lymphoma or childhood lymphoma at this time; neither title being accurate or satisfactory. A proposal that it should be called Burkitt lymphoma was half-accepted. Not all delegates were prepared to accept that it is a lymphoma so it was named Burkitt tumour. I was asked to give presentation on the cytology and histochemistry of malignant lymphoma in Uganda. The request for cytology came as a shock because it had not been our custom to use this technique. In our rapid recovery act, we discovered that Burkitt lymphoma makes excellent imprint preparations and has very characteristic cytological features (Wright, 1964a). The World Health Organization (WHO) organized a meeting at the National Cancer Institute in Washington in 1967 to discuss the nature of Burkitt lymphoma and its relationship to other lymphomas. It was agreed at the meeting that the lymphoma should be defined on its morphology (histology and cytology) not by its clinical features. In more recent years, immunohistochemistry has been used to support this diagnosis. Burkitt lymphomas express B-cell markers, they are CD10-positive and BCL2-negative. Proliferation markers show that 100% of the tumours are in cycle. The current WHO classification of lymphomas includes two eponymous tumours: Hodgkin lymphoma and Burkitt lymphoma (Swerdlow et al, 2008). Thomas Hodgkin described six cases of lymphadenopathy based on their gross morphological appearances in 1832 (Kass & Kass, 1988). After review 100 years later, including histology on some cases where tissue was available, it was concluded that only three of the original cases were what we would now recognize as Hodgkin lymphoma. Burkitt lymphoma has suffered a reverse fate. The current WHO classification identifies four categories of Burkitt lymphoma (Table 1), only one of which (endemic Burkitt lymphoma) corresponds to the tumour described by Burkitt. The morphological and immunohistochemical similarity of these tumours relates to the fact that all show deregulation of the MYC gene resulting from the translocations of that gene. It might be assumed that ‘endemic’ means those cases occurring in the wet tropics of Africa and Papua New Guinea. However, cases from these areas identified by morphology alone will include acquired immunodeficiency syndrome (AIDS)-related Burkitt lymphoma and possibly sporadic Burkitt lymphoma. Clinical features need to be taken into account in categorizing these cases. AIDS-related Burkitt lymphoma occurs in young HIV-positive adults and presents most commonly with peripheral lymphadenopathy and abdominal masses (Table 2, Wright, 1964b). Sporadic Burkitt lymphoma occurs in children and young adults and involves peripheral lymph nodes, oropharynx and terminal ileum, which are not common sites for endemic Burkitt lymphoma (Table 3, Wright et al, 1997). Sporadic Burkitt lymphoma more commonly involves the bone marrow than endemic Burkitt lymphoma. There will be cases in which the clinical features may not clearly differentiate endemic and sporadic Burkitt lymphoma. For example, ovarian tumours may be seen in sporadic Burkitt lymphoma. Very rare cases of Burkitt lymphoma seen in children outside the wet tropics have jaw tumours and visceral tumours characteristic of the endemic tumour (Wright, 1966). These cases deserve more intensive study.